Skip to main content

Advertisement

Log in

IL-2 and IFN-gamma in the retina of diabetic rats

  • Basic Science
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

The pathophysiology of the early events leading to diabetic retinopathy is not fully understood. It has been suggested that Inflammatory processes are involved in the development of the disease; however, the concentrations of tissue retinal inflammatory mediators and their possible alteration in diabetic retinopathy have not been described. The aim of this work was to study T-helper cell cytokine and chemokine profiles, and tyrosine nitration in retinal tissue of diabetic rats.

Methods

Cytokines (interleukin IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-10, TNFa, GM-CSF, IFN-g), chemokines (MIP-1a, MIP-2, MIP-3a, MCP-1, GRO/KC, RANTES, Fractalkine), and tyrosine nitration were measured in retinal homogenate obtained from Long–Evans rats after 5 months of experimental diabetes.

Results

The T-helper type 1 cytokines IL-2 and INF-gamma, in addition to NO production (measured as nitrotyrosine), were found to be significantly elevated in diabetic rat retina homogenates. None of the other cytokines and chemokines studied were affected by the diabetic condition.

Conclusions

Immunoregulatory cytokines belonging to the Th-1 group (IL-2 and IFN-gamma) were increased in the retina of experimental diabetic rats. Moreover, the nitrotyrosine formation (as an expression of increased NO production) was significantly elevated in the diabetic retina, supporting the concept of an inflammatory element in the development of diabetic retinopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chu J, Ali Y (2008) Diabetic retinopathy: a review. Drug Development Research 69:1–14

    Article  CAS  Google Scholar 

  2. Kern TS (2007) Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res 2007:95103

    PubMed  Google Scholar 

  3. Schroder S, Palinski W, Schmid-Schonbein GW (1991) Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy. Am J Pathol 139:81–100

    CAS  PubMed  Google Scholar 

  4. Miyamoto K, Khosrof S, Bursell SE, Rohan R, Murata T, Clermont AC, Aiello LP, Ogura Y, Adamis AP (1999) Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA 96:10836–10841

    Article  CAS  PubMed  Google Scholar 

  5. Boeri D, Maiello M, Lorenzi M (2001) Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 50:1432–1439

    Article  CAS  PubMed  Google Scholar 

  6. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, Adamis AP (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. Faseb J 16:438–440

    CAS  PubMed  Google Scholar 

  7. Kowluru RA, Odenbach S (2004) Role of interleukin-1beta in the pathogenesis of diabetic retinopathy. Br J Ophthalmol 88:1343–1347

    Article  CAS  PubMed  Google Scholar 

  8. Vincent JA, Mohr S (2007) Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56:224–230

    Article  CAS  PubMed  Google Scholar 

  9. Abu el Asrar AM, Maimone D, Morse PH, Gregory S, Reder AT (1992) Cytokines in the vitreous of patients with proliferative diabetic retinopathy. Am J Ophthalmol 114:731–736

    CAS  PubMed  Google Scholar 

  10. Tang S, Scheiffarth OF, Thurau SR, Wildner G (1993) Cells of the immune system and their cytokines in epiretinal membranes and in the vitreous of patients with proliferative diabetic retinopathy. Ophthalmic Res 25:177–185

    Article  CAS  PubMed  Google Scholar 

  11. Meleth AD, Agron E, Chan CC, Reed GF, Arora K, Byrnes G, Csaky KG, Ferris FL 3rd, Chew EY (2005) Serum inflammatory markers in diabetic retinopathy. Invest Ophthalmol Vis Sci 46:4295–4301

    Article  PubMed  Google Scholar 

  12. Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA (2006) Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: Implications for structural differences in macular profiles. Exp Eye Res 82:798–806

    Article  CAS  PubMed  Google Scholar 

  13. Maier R, Weger M, Haller-Schober EM, El-Shabrawi Y, Wedrich A, Theisl A, Aigner R, Barth A, Haas A (2008) Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Mol Vis 14:637–643

    CAS  PubMed  Google Scholar 

  14. Murugeswari P, Shukla D, Rajendran A, Kim R, Namperumalsamy P, Muthukkaruppan V (2008) Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and Eales’ disease. Retina 28:817–824

    Article  PubMed  Google Scholar 

  15. Vijay SK, Mishra M, Kumar H, Tripathi K (2009) Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes. Acta Diabetol 46:27–33

    Article  CAS  PubMed  Google Scholar 

  16. ter Steege JC, Koster-Kamphuis L, van Straaten EA, Forget PP, Buurman WA (1998) Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA. Free Radic Biol Med 25:953–963

    Article  PubMed  Google Scholar 

  17. Singh VK, Mehrotra S, Narayan P, Pandey CM, Agarwal SS (2000) Modulation of autoimmune diseases by nitric oxide. Immunol Res 22:1–19

    Article  CAS  PubMed  Google Scholar 

  18. Gustavsson C, Agardh CD, Hagert P, Agardh E (2008) Inflammatory markers in nondiabetic and diabetic rat retinas exposed to ischemia followed by reperfusion. Retina 28:645–652

    Article  PubMed  Google Scholar 

  19. Nehme A, Edelman J (2008) Dexamethasone inhibits high glucose-, TNF-alpha-, and IL-1beta-induced secretion of inflammatory and angiogenic mediators from retinal microvascular pericytes. Invest Ophthalmol Vis Sci 49:2030–2038

    Article  PubMed  Google Scholar 

  20. Kowluru RA, Odenbach S (2004) Role of interleukin-1beta in the development of retinopathy in rats: effect of antioxidants. Invest Ophthalmol Vis Sci 45:4161–4166

    Article  PubMed  Google Scholar 

  21. Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, Levison SW (2005) Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54:1559–1565

    Article  CAS  PubMed  Google Scholar 

  22. Olejniczak K, Kasprzak A (2008) Biological properties of interleukin 2 and its role in pathogenesis of selected diseases—a review. Med Sci Monit 14:RA179–RA189

    CAS  PubMed  Google Scholar 

  23. Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N, Kaiser A, Hinrichs CS, Klebanoff CA, Tagaya Y, Restifo NP (2006) Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J Immunol 176:5255–5266

    CAS  PubMed  Google Scholar 

  24. Dmoszynska A, Kandefer-Szerszen M, Rolinski J, Legiec W, Kaminska T (1999) Influence of low dose rIL-2 treatment on endogenous cytokine production, expression of surface IL-2R and the level of soluble IL-2R in patients with minimal residual disease. Leuk Lymphoma 35:355–366

    Article  CAS  PubMed  Google Scholar 

  25. Kuhn DJ, Dou QP (2005) The role of interleukin-2 receptor alpha in cancer. Front Biosci 10:1462–1474

    Article  CAS  PubMed  Google Scholar 

  26. Bien E, Balcerska A, Kuchta G (2007) Serum level of soluble interleukin-2 receptor alpha correlates with the clinical course and activity of Wilms’ tumour and soft tissue sarcomas in children. Biomarkers 12:203–213

    Article  CAS  PubMed  Google Scholar 

  27. Doganay S, Evereklioglu C, Er H, Turkoz Y, Sevinc A, Mehmet N, Savli H (2002) Comparison of serum NO, TNF-alpha, IL-1beta, sIL-2R, IL-6 and IL-8 levels with grades of retinopathy in patients with diabetes mellitus. Eye 16:163–170

    Article  CAS  PubMed  Google Scholar 

  28. Matteucci E, Malvaldi G, Fagnani F, Evangelista I, Giampietro O (2004) Redox status and immune function in type I diabetes families. Clin Exp Immunol 136:549–554

    Article  CAS  PubMed  Google Scholar 

  29. Geiger K, Howes E, Gallina M, Huang XJ, Travis GH, Sarvetnick N (1994) Transgenic mice expressing IFN-gamma in the retina develop inflammation of the eye and photoreceptor loss. Invest Ophthalmol Vis Sci 35:2667–2681

    CAS  PubMed  Google Scholar 

  30. Miranda M, Muriach M, Romá J, Bosch-Morell F, Genovés JM, Barcia J, Araiz J, Diaz-Llopis M, Romero FJ (2006) Oxidative stress in a model of experimental diabetic retinopathy. II. Peroxynitrite scavengers utility. Arch Soc Esp Oftalmol 80:27–32

    Google Scholar 

  31. Yuan Z, Feng W, Hong J, Zheng Q, Shuai J, Ge Y (2009) p38MAPK and ERK promote nitric oxide production in cultured human retinal pigmented epithelial cells induced by high concentration glucose. Nitric Oxide 20:9–15

    Article  CAS  PubMed  Google Scholar 

  32. Gesbert F, Delespine-Carmagnat M, Bertoglio J (1998) Recent advances in the understanding of interleukin-2 signal transduction. J Clin Immunol 18:307–320

    Article  CAS  PubMed  Google Scholar 

  33. Martino A, JHt H, Lord JD, Moon JJ, Nelson BH (2001) Stat5 and Sp1 regulate transcription of the cyclin D2 gene in response to IL-2. J Immunol 166:1723–1729

    CAS  PubMed  Google Scholar 

  34. Moon JJ, Rubio ED, Martino A, Krumm A, Nelson BH (2004) A permissive role for phosphatidylinositol 3-kinase in the Stat5-mediated expression of cyclin D2 by the interleukin-2 receptor. J Biol Chem 279:5520–5527

    Article  CAS  PubMed  Google Scholar 

  35. Shio MT, Olivier M, Jancar S, Ribeiro-Dias F (2008) Crucial cytokine interactions in nitric oxide production induced by Mycoplasma arthritidis superantigen. Microbes Infect 10:1543–1551

    Article  CAS  PubMed  Google Scholar 

  36. Kern TS, Tang J, Mizutani M, Kowluru RA, Nagaraj RH, Romeo G, Podesta F, Lorenzi M (2000) Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia. Invest Ophthalmol Vis Sci 41:3972–3978

    CAS  PubMed  Google Scholar 

  37. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187

    Article  CAS  PubMed  Google Scholar 

  38. Ogden CA, Elkon KB (2006) Role of complement and other innate immune mechanisms in the removal of apoptotic cells. Curr Dir Autoimmun 9:120–142

    CAS  PubMed  Google Scholar 

  39. Wu Y, Tibrewal N, Birge RB (2006) Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol 16:189–197

    Article  CAS  PubMed  Google Scholar 

  40. Ren G, Su J, Zhao X, Zhang L, Zhang J, Roberts AI, Zhang H, Das G, Shi Y (2008) Apoptotic cells induce immunosuppression through dendritic cells: critical roles of IFN-gamma and nitric oxide. J Immunol 181:3277–3284

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Francisco Javier Romero.

Additional information

A financial relationship with the Conselleria de Educación exists in form of a Grant. The authors have full control of all primary data, and we agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review our data upon request.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnsen-Soriano, S., Sancho-Tello, M., Arnal, E. et al. IL-2 and IFN-gamma in the retina of diabetic rats. Graefes Arch Clin Exp Ophthalmol 248, 985–990 (2010). https://doi.org/10.1007/s00417-009-1289-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-009-1289-x

Keywords

Navigation